The present invention relates to the field of prodrugs of chemotherapeutic agents and method of use thereof.
U.S. Pat. No. 4,786,495 to Bird discloses flurbiprofen and salts thereof in admixture with an excipient encompassing fatty acid esters such as polyol esters of polyethylene glycol.
U.S. Pat. No. 5,681,964 to Ashton relates to soluble ester prodrugs of polyethylene glycol and various chemotherapeutic agents.
U.S. Pat. No. 4,767,751 to David discloses polyethylene glycol type solubilizers for flurbiprofen U.S. Pat. No. 4,613,505 to Mizushima discloses esters of flurbiprofen which may be dissolved in a vegetable oil and emulsified.
U.S. Pat. Nos. 4,489,080 and 4,443,476 to Lomen discloses alkyl esters of flurbiprofen.
U.S. Pat. No. 4,477,468 to Heckler discloses the systemic administration and topical application of flurbiprofen, salts thereof and esters thereof. The esters are (C1-C8) alkyl esters and are prescribed for the prophylactic and therapeutic treatment of herpes type II virus. U.S. Pat. Nos. 4,473,584, 4,443,476 and 4,439,451 are related to U.S. Pat. No. 4,477,468.
U.S. Pat. No. 4,412,994 to Sloan discloses hydroxamic derivatives of flurbiprofen as prodrugs
U.S. Pat. No. 4,206,220 relates to compounds that are similar to those of U.S. Pat. No. 4,412,994. These compounds are aminoxy derivatives of, e.g., flurbiprofen.
U.S. Pat. No. 4,009,283 to Herr et al discloses lower alkyl esters of flurbiprofen. The esters are lower alkyl esters.
Canadian Patent CA 1,148,165 and German Patent DE 3,811,118 disclose esters of flurbiprofen.
The anti-inflammatory agent, flurbiprofen, produces local irritation when applied for treatment of inflammation. Various techniques have been used to lower the dosage of flurbiprofen to the patient, such as techniques for rapid release of flurbiprofen into the body. Nevertheless, there exists a need in the art for compositions that achieve the desired effects of flurbiprofen without the concomittant local irritation. This is particularly true in the application of the flurbiprofen anti-inflammatory agent to the eye.
An advantage of the present invention is to provide covalent conjugates of chemotherapeutic agents with mono- di- and polyoxaalkanoic or thiaalkanoic acids.
A further advantage of the present invention is the ability to adjust the solubility of steroidal molecules, lipophilicity and their half-life in the body and thus, bioavailability, by altering the structure and length of the oxaalkanoic acid or polyoxaalkanoic acid chain.
A further advantage of the present invention is to provide compounds having a chemotherapeutic effect which avoids or reduces the local irritation brought about by administration of the parent drug.
Another advantage of the present invention is to provide a pharmaceutical composition comprising a compound having a chemotherapeutic effect, but a reduced local irritation as compared to that produced by the parent drug.
Yet another advantage of the present invention is the ability of the prodrugs to permeate biological membranes, for example, the stratum corneum, and remain there until enzymatically cleaved, can be enhanced.
Additional advantages of the present invention will be set forth in the description which follows and in part will become apparent to those having ordinary skill in the art upon examination of the following or may be learned from the practice of the present invention. The objects and advantages of the invention may be realized and obtained as particularly pointed out in the appended claims.
According to the present invention, the foregoing and other advantages are achieved in part by providing a prodrug composition comprising a chemotherapeutic agent linked to a variety of oxaatkanoic acids of the formulas shown in Structures 1 and 2 wherein n=1-12. In a preferred embodiment n=1-6.
Additional advantages of the present invention will become readily apparent to those skilled in this art from the following detailed description, wherein embodiments of the present invention are described simply by way of illustrating of the best mode contemplated in carrying out the present invention. As will be realized, the present invention is capable of other and different embodiments, and its several details are capable of modifications in various obvious respects, all without departing from the present invention. Accordingly, the drawings and description are to be regarded as illustrative in nature and not as restrictive.